More on d4T and mitochondria: Drug’s effect on mt-DNA is ‘blunted’

Further investigation of participants in Gilead’s 903 study, a comparison of tenofovir and d4T as first-line HIV therapy, has revealed differences in the drugs’ effects on cellular components known as mitochondria. These effects underpin the greater frequency of certain adverse events noted in the d4T arm of this study.

The 903 trial recruited 600 treatment-naïve individuals with viral loads above 5,000 copies to this ongoing three year study. Participants received efavirenz and 3TC, plus either tenofovir or d4T which were allocated at random and blinded by placebo. A planned interim analysis at week 48 found no differences in efficacy between the two arms. Efficacy data from the 903 study were presented at the Fourteenth International AIDS Conference in Barcelona this July, and reported here on aidsmap.com.

Whilst the study reported no overall differences in the frequency of grade 3 or 4 adverse events between arms, d4T recipients were more likely to experience increases in triglycerides, total cholesterol and LDL cholesterol. These differences remained regardless of whether fasted or non-fasted values were analysed.

North American participants in this international trial were entered into a sub-study which investigated the effects of the different treatments on mitochondrial DNA, and compared these with an HIV-negative control group. Amongst the one hundred and thirteen tenofovir recipients, mitochondrial DNA rose from an average of 239 copies/cell at baseline to 321 copies/cell at week 48. Montaner and colleagues have previously reported lower mitochondria levels in HIV infection; an observation supported here – the average mt-DNA level was 321 copies/cell amongst the 49 control patients. In comparison to the tenofovir arm, the 114 d4T recipients gained less mitochondria, rising from a baseline average of 256 copies/cell to 284 copies/cell at week 48.

But what’s the clinical significance of these differences? One possible outcome of mitochondrial toxicity is known to be an increase in lactate levels in the blood. In extreme cases this results in lactic acidosis, which can be fatal. Whilst abnormal lactate levels were seen more frequently amongst d4T recipients (36% versus 7%), these changes were asymptomatic and did not require modification of HIV therapy.

As previously reported, the frequency of any mitochondrial toxicity-related adverse events after 48 weeks was greater in the d4T arm than the tenofovir arm (10% versus 3%). This difference was largely explained by the greater frequency of neuropathy amongst d4T users (7% versus 2%).

In closing his presentation to the 42nd ICAAC in San Diego today, lead investigator Joel Gallant said: “Even at 48 weeks there is a suggestion that there’s a difference in the long-term toxicities of these regimens.”